capillary electrophoresis in global emerging markets:...
TRANSCRIPT
Capillary Electrophoresis in Global
Emerging Markets A Regulatory
Perspective
Brian K Nunnally PhD
Agenda
The Lifecycle Approach ndash a guidance review
What it really meanshellip
Global Emerging Markets and their impact on the CE
professional
Selected questions and their answers
Lifecycle management guidance
Health Canada published one in 2004 (GUI-0029)
It was revised in 2009
The activities relating to validation studies may be
classified into three phases
- Phase 1 Pre-Validation Phase or the Qualification Phase
- Phase 2 Process Validation Phase (Process Qualification
phase)
- Phase 3 Validation Maintenance Phase
Other recent guidances have been published by FDA
and EMA (draft)
The guidance is specific to Process Validation however it can be
applied to analytical as well
Process Validation Guidance from FDA (2011)
The guidance aligns process validation activities with the
product lifecycle concept and with existing FDA
guidance
The lifecycle concept links product and process
development qualification of the commercial
manufacturing process and maintenance of the process
in a state of control during routine commercial
production
The concept aligns with expectations for the analytical
validation and ongoing laboratory data generation
FDA Guidance Process validation stages
Stage 1 ndash Process Design development and scale-up
activities
Stage 2 ndash Process Qualification Proof of reproducible
commercial manufacturing
Stage 3 ndash Continued Process Verification Ongoing
assurance of process control
FDA Guidance Process validation stages ndash
applied to the analytical laboratory
Stage 1 ndash Analytical Method Design development and
initial qualification activities
Stage 2 ndash Analytical Method Qualification Proof of
reproducible commercial testing
Stage 3 ndash Continued Analytical Method Verification
Ongoing assurance of analytical control
Expectations of the CE professional
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
ultimately on product attributes
Control the variation in a manner commensurate with the
risk it represents to the process and product
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Agenda
The Lifecycle Approach ndash a guidance review
What it really meanshellip
Global Emerging Markets and their impact on the CE
professional
Selected questions and their answers
Lifecycle management guidance
Health Canada published one in 2004 (GUI-0029)
It was revised in 2009
The activities relating to validation studies may be
classified into three phases
- Phase 1 Pre-Validation Phase or the Qualification Phase
- Phase 2 Process Validation Phase (Process Qualification
phase)
- Phase 3 Validation Maintenance Phase
Other recent guidances have been published by FDA
and EMA (draft)
The guidance is specific to Process Validation however it can be
applied to analytical as well
Process Validation Guidance from FDA (2011)
The guidance aligns process validation activities with the
product lifecycle concept and with existing FDA
guidance
The lifecycle concept links product and process
development qualification of the commercial
manufacturing process and maintenance of the process
in a state of control during routine commercial
production
The concept aligns with expectations for the analytical
validation and ongoing laboratory data generation
FDA Guidance Process validation stages
Stage 1 ndash Process Design development and scale-up
activities
Stage 2 ndash Process Qualification Proof of reproducible
commercial manufacturing
Stage 3 ndash Continued Process Verification Ongoing
assurance of process control
FDA Guidance Process validation stages ndash
applied to the analytical laboratory
Stage 1 ndash Analytical Method Design development and
initial qualification activities
Stage 2 ndash Analytical Method Qualification Proof of
reproducible commercial testing
Stage 3 ndash Continued Analytical Method Verification
Ongoing assurance of analytical control
Expectations of the CE professional
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
ultimately on product attributes
Control the variation in a manner commensurate with the
risk it represents to the process and product
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Lifecycle management guidance
Health Canada published one in 2004 (GUI-0029)
It was revised in 2009
The activities relating to validation studies may be
classified into three phases
- Phase 1 Pre-Validation Phase or the Qualification Phase
- Phase 2 Process Validation Phase (Process Qualification
phase)
- Phase 3 Validation Maintenance Phase
Other recent guidances have been published by FDA
and EMA (draft)
The guidance is specific to Process Validation however it can be
applied to analytical as well
Process Validation Guidance from FDA (2011)
The guidance aligns process validation activities with the
product lifecycle concept and with existing FDA
guidance
The lifecycle concept links product and process
development qualification of the commercial
manufacturing process and maintenance of the process
in a state of control during routine commercial
production
The concept aligns with expectations for the analytical
validation and ongoing laboratory data generation
FDA Guidance Process validation stages
Stage 1 ndash Process Design development and scale-up
activities
Stage 2 ndash Process Qualification Proof of reproducible
commercial manufacturing
Stage 3 ndash Continued Process Verification Ongoing
assurance of process control
FDA Guidance Process validation stages ndash
applied to the analytical laboratory
Stage 1 ndash Analytical Method Design development and
initial qualification activities
Stage 2 ndash Analytical Method Qualification Proof of
reproducible commercial testing
Stage 3 ndash Continued Analytical Method Verification
Ongoing assurance of analytical control
Expectations of the CE professional
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
ultimately on product attributes
Control the variation in a manner commensurate with the
risk it represents to the process and product
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Process Validation Guidance from FDA (2011)
The guidance aligns process validation activities with the
product lifecycle concept and with existing FDA
guidance
The lifecycle concept links product and process
development qualification of the commercial
manufacturing process and maintenance of the process
in a state of control during routine commercial
production
The concept aligns with expectations for the analytical
validation and ongoing laboratory data generation
FDA Guidance Process validation stages
Stage 1 ndash Process Design development and scale-up
activities
Stage 2 ndash Process Qualification Proof of reproducible
commercial manufacturing
Stage 3 ndash Continued Process Verification Ongoing
assurance of process control
FDA Guidance Process validation stages ndash
applied to the analytical laboratory
Stage 1 ndash Analytical Method Design development and
initial qualification activities
Stage 2 ndash Analytical Method Qualification Proof of
reproducible commercial testing
Stage 3 ndash Continued Analytical Method Verification
Ongoing assurance of analytical control
Expectations of the CE professional
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
ultimately on product attributes
Control the variation in a manner commensurate with the
risk it represents to the process and product
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
FDA Guidance Process validation stages
Stage 1 ndash Process Design development and scale-up
activities
Stage 2 ndash Process Qualification Proof of reproducible
commercial manufacturing
Stage 3 ndash Continued Process Verification Ongoing
assurance of process control
FDA Guidance Process validation stages ndash
applied to the analytical laboratory
Stage 1 ndash Analytical Method Design development and
initial qualification activities
Stage 2 ndash Analytical Method Qualification Proof of
reproducible commercial testing
Stage 3 ndash Continued Analytical Method Verification
Ongoing assurance of analytical control
Expectations of the CE professional
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
ultimately on product attributes
Control the variation in a manner commensurate with the
risk it represents to the process and product
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
FDA Guidance Process validation stages ndash
applied to the analytical laboratory
Stage 1 ndash Analytical Method Design development and
initial qualification activities
Stage 2 ndash Analytical Method Qualification Proof of
reproducible commercial testing
Stage 3 ndash Continued Analytical Method Verification
Ongoing assurance of analytical control
Expectations of the CE professional
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
ultimately on product attributes
Control the variation in a manner commensurate with the
risk it represents to the process and product
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Expectations of the CE professional
Understand the sources of variation
Detect the presence and degree of variation
Understand the impact of variation on the process and
ultimately on product attributes
Control the variation in a manner commensurate with the
risk it represents to the process and product
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Understanding variability
Variability comes in three
forms process sample
and analytical
A control chart of the lot
release values will
encompass all three forms
of variability
It is rare that all three types
can be accurately
quantitated without a
carefully planned and
executed hierarchical or
similar study
σsup2 = σsup2P + σsup2S + σsup2T
Where
σsup2 = Total variance
σsup2P = Process variance
σsup2S = Sampling variance
σsup2T = Test variance
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Illustrating Stability
0
2
4
6
8
10
12
14
0 5 10 15 20 25 30 35 40 45 50
If the points fall at random about the centreline
and remain within the control limits the
process is deemed to be stable
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Illustrating Instability
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
If this red line is the test specification
should we react to the ldquospecial causerdquo
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
A better way
0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 500
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30 35 40 45 50
Re-drawing the limits makes it easy to see
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
17
18
19
20
21
22
23
24
25
26
27
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43
15
17
19
21
23
25
27
29
31
33
35
1 4 7 10
13
16
19
22
25
28
31
34
37
40
43
Production Data Laboratory Controls
Where Lies The Problem Limits are set as per the usual practice plusmn 3 sigma
Understanding the data
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
18
19
20
21
22
23
24
25
26
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
05
1
15
2
25
3
35
4
45
5
Ran
ge
20
22
24
26
28
30
32
34
0 5 10 15 20 25 30 35 40 45 50
1-P
oint
Ave
rage
0
2
4
6
8
10
12
Ran
ge
Understanding the data
Shewhart Control Charts are Usedhellip
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Global Emerging Markets
For most life cycle management activites focus on the
ldquoreferencerdquo markets eg US EMA Canada Japan
There are of course hundreds of other markets
The prominent and fast growing are referred to as Global
Emerging Markets
These markets are becoming strategically important for
the pharmaceutical industry
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Argentina
Bahrain
Bangladesh
Brazil
Chile
China
Colombia
Egypt
Hong Kong
India
Indonesia
Israel
Jordan
Kuwait
Malaysia
Mauritius
Mexico
Morocco
Nigeria
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Global Emerging Markets
Country IMFNext-
11BRICCIVETS FTSE MSCI
THE
ECONOMI
ST
SampPDOW
JONESBBVA
Columbia
University
EMGP
Oman
Pakistan
Peru
Philippines
Qatar
Russia
Saudi Arabia
Singapore
South Africa
South Korea
Sri Lanka
Taiwan
Thailand
Tunisia
Turkey
UAE
Ukraine
Venezuela
Vietnam
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Characteristics of GEM Regulatory Agencies
Many markets expect a major market (eg US or EMA)
approval before filing
- This facilitates approval in these countries
- Notable exceptions South Africa Brazil
Requirements and expertise can vary widely but both
are increasing
- Example Azerbaijan vs Russia vs India
- Example HSA (Singapore)
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
GEM Challenges
Regulations are evolving
- Advances ICH Pharmaceutical Inspection Coop Scheme
Regulations and guidelines (along with unstated
expectations) are not globally harmonized - Many country or region-specific requirements and interpretation of
guidance
- Pharmacopeia standards differ country to country
- GMPs are not globally harmonized
- Inspections are not globally harmonized
- Differences exist for reviewapproval times clinical trial application
content specification
- Approval of changes is not harmonized
- Post approval reporting requirements are not harmonized
18
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
GEM Challenges
Increasing complexity with foreign countries
bull Language time zones culture FMAs in-country testing
availability of instrumentation technical savvy
New requirements for some GEM countries
IP issues
Inspections
Multiple approved dossier versions for a single drug
- Multiple specifications multiple item codes different CoAs
different responses to questions
Overall Global CTD not possible
Understanding both the intent and expectations of
questions
19
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
In-country testing
Many countries require in country testing either before
approval or after launch of the product
Capillary electrophoresis (among other methodologies)
can be a challenge for some markets
Methods need to be robust () to facilitate transfer to
these markets
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
In-country testing (example)
Country Mandatory Requirement
Small Molecules Biologicals
Full vs Partial testing Local vs Contract Lab
Argentina Yes Yes Full Local Lab mandated
Brazil Yes NA Full Local Lab mandated
Chile Yes Yes Partial is possible Can be contracted out
Uruguay Yes Yes Theoretically full testing selected possible Can be contracted out
Mexico Yes Yes Full Testing (for n=20 batches) Then request a
reduction If tests are too expensive or require
sophisticated equipment reduction is possible
Testing is exempted for orphan drugs
Can be contracted out
Russia Yes Yes Full testing for new registrations Laboratory assigned by
MoH
Turkey Yes Yes Tests performed are based on the product but
normally these include Biological Dissolution
Physical physicochemical controls Content
uniformity amount Microbiological purity and ID
Official analysis institution
of TMOH
Ukraine Yes Yes Full testing State local laboratory
assigned by the MoH
Israel Yes Yes Full testing for the first imported batch and then
upon MoH request
Testing carried out by
MOH Lab
Other countries requiring testing Costa Rica DR El Salvador Ecuador Guatemala Honduras
Nicaragua Panama South Korea etc
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
GEM Requirements (examples) Brazil (Resolution RDC No 17 16 Apr 2010)
Article 19 Qualification and validation should not be considered only
exercises After the adoption of the qualification andor validation
report it there should have a continuous monitoring program which
must be based on periodic review [Note software validation and re-
validation is called out as a specific self-inspection item]
Article 209 Sole Paragraph Compendial analytical methods do not
require validation but before its implementation there must be
documented evidence of their suitability in the laboratory operating
conditions
Article 312 sect 3 The pharmacopoeial methods should be used for the
validation and performance of the sterility test
Article 463 sect 2 The retrospective validation is no longer encouraged
and is not applicable to the manufacture of sterile products
Article 479 sect 2 A risk assessment should be used to determine the
scope and extent of validation 22
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
GEM Requirements (examples) Thailand (QampA on ASEAN Analytical Validation)
6 Identify the conditionsscenarios when each of the following is
required to be conducted Full validation Revalidation Verification
Refer to 1 for Full validation and Verification According to ASEAN
Guideline revalidation may be required in the following circumstances
- Change in the synthesis of the drug substance
- Change in the composition of the finished product
- Change in the analytical procedure
From ASEAN Guideline on Analytical Validation (consistent with ICH)
The compendial methods are not required to be validated but merely
verify their suitability under actual conditions of use
23
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
GEM Requirements (examples) ASEAN Variation Guideline for Pharmaceutical
Products
Major Variation
- No analytical examples (not counting specification changes)
Minor Variation - Prior Approval (MiV-PA)
- Change of test procedure to non-compendial drug substance (must at
least show equivalence to former procedure) ndash MiV-PA9
- Change of in-process controls applied during the manufacture of the drug
substance (including tightening and addition of new in-process test) ndash MiV-
PA6
- Change of in-process controls applied during the manufacture of the drug
product (including tightening and addition of new in-process test) ndash MiV-
PA19
bull Interesting note Any new test method does not concern a novel non-standard
technique or a standard technique used in a novel way
Minor Variation - Notification (MiV-N)
- No analytical examples
24
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
GEM Requirements (examples) South Africa (Amendments)
Four categories
- Type A - amendments that may be implemented without intervention of or prior
notification to Council
- Type B - amendments that require prior notification
- Type C - amendments that require prior approval
- Type D - amendments that should be considered new applications
Type A Biological examples
- (25) Addition of release tests and or of specifications or tightening of
specifications for intermediates of the APIs
Type B Biological examples
- No analytical examples
25
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
GEM Requirements (examples) South Africa (Amendments)
Type C Biological examples
- (19B) Any change in analytical methods that
bull results in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establishes a new analytical method
bull deletes a specification or an analytical method
bull eliminates tests from the stability protocol or
bull alters the acceptance criteria of the stability protocol
- (20B) Any change in production processes that may
bull result in change(s) of specification limits or modification(s) in potency
sensitivity specificity or purity
bull establish a new analytical method
bull delete a specification or an analytical method
bull eliminate tests from the stability protocol or
bull alter the acceptance criteria of the stability protocol
26
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Analytical Validation and Method Detail
(several)
Question Asked a series of questions on method details
requested method validation data for all methods used in
the analytical control strategy
Answer
- Provided copies of the methods and answered the specific
detail questions requested
- Some requests have included providing raw data (eg real
weight of reference standard and sample used) from validation
- This detail is requested as a substitute for in-country testing
thus preventing the need for in-country (repeat) testing
- The procedures are not considered ldquopart of the licenserdquo
Result Success
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Method detail (South Korea)
Question Detailed test methods for API
Answer
- Provided descriptions of the assays but not copies of the methods
- These are not considered ldquopart of the licenserdquo (eg The detailed test
methods for Drug Substance are supplied as a reference The
information provided in Module 3 Section 32S42 Analytical
Procedures is considered to contain the regulatory information and
requirements)
Result Success
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Detailed data (several)
Question Provide chromatograms and electropherograms for all
stability timepoints
Answer
- Provided chromatogramselectropherograms sometimes providing only
one lot instead of three lots
Result Success
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Conclusions
Understanding analytical methods including real time
assessments of variability are becoming increasingly
important
The trends toward increased globalization will create
additional work and challenge for analytical professionals
Global Emerging Markets will become a larger portion of
the work due to increasing complexity in these markets
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Acknowledgements
Catherine Anderson
Helena Madden
Sue Stella
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf
Guidance list (non-inclusive) Region Topic ASEAN ASEAN GUIDELINE ON SUBMISSION OF MANUFACTURING PROCESS VALIDATION DATA FOR DRUG REGISTRATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar96657FiledatA
SEAN20PV20(Version2031)20Main20Guide20without20annexespdf ASEAN VARIATION GUIDELINE FOR PHARMACEUTICAL PRODUCTS
httpwwwfdagovphattachmentsarticle95567ASEAN20Variation20Guideline20for20Pharmaceutical20Products20Final20
Draft207220(2013)pdf Thailand QampA on ASEAN Analytical Validation
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationwestern_medicinesfiles_guidelinesPar98887FiledatQ
ampA20analytical20validation-25jun55pdf ASEAN website with links to several guidances
httpwwwaseanorgcommunitiesasean-economic-communityitemharmonization-of-standards-and-technical-requirements-in-asean Brazil Resolution RDC No 27
httpwwwemergogroupcomfilesbrazil-resolution-rdc-no-27-21-june-2011pdf
Establishes Minimum Requirements for the Validation of Bioanalytical Methods Used in Pre- and Post-Marketing Studies
The validation of the analytical methods (Resolution RE 899 (IDRAC 39212) of 29-May-20033 and Resolution RDC 27 (IDRAC 143541) of
17-May-2012) is mandatory whenever the method is an in-house method or it is not described in pharmacopeias accepted by ANVISA Resolution RDC No 17
httpwwwabiquifiorgbrlegislacaoanvisaingles_rdc17pdf
16-Apr-2010 presents detailed guidelines about the validation and qualification requirements in the pharmaceutical industry as part of the
Good Manufacturing Practices Regulation Australia Note for Guidance on Validation of Analytical Procedures Text and Methodology
CPMPICH38195 (pdf183kb)
Japan Excerpt from presentation Japan has no guidance for bioanalytical method validation The answers in these slides are the results of the
discussion in the JBF kickoff meeting on March 30 (2011)1048579
httpwwwnihsgojpdrugBMVMontreal20110414_katoripdf Malaysia httpportalbpfkgovmyaeimagesFileAnalytical_Validation_Documents_of_Injections_Submission_Guidelinespdf Singapore ANALYTICAL METHOD VALIDATION
httpwwwhsagovsgpublishetcmedialibhsa_libraryhealth_products_regulationgmpfiles_1Par23186FiledatGUIDE-MQA-012A-
004pdf